Large-scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease

Abstract

Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson’s Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson’s disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal–lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.

Genetic Risk Profiling in Parkinson’s Disease and Utilizing Genetics to Gain Insight into Disease-Related Biological Pathways

“…The MSigDB was used to extract gene sets representative of biological pathways, and a pathway-specific polygenic effect score was constructed for each dataset. In support of the previous pathway-specific analyses [ 36 , 37 ], the study found a significant association between PD risk and the endocytic membrane trafficking and mitochondrial function pathways [ 38 ]. Most notably, this approach identified significant associations between risk of PD and novel biological pathways.…”

“…Overall, the study concluded that the main contributors to PD etiology are molecular processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid metabolism, synaptic transmission, endosomal–lysosomal dysfunction and apoptosis mediated by initiator and executioner caspases ( Figure 2 ). This was the first study to test the contribution of thousands of molecular processes to PD risk in an unbiased and data-driven manner and provide a foundational resource for the PD community through a publicly available pathways browser [ 38 ] ( ).…”

“…Similar single-cell transcriptomics in the mouse nervous system also confirm the association between dopaminergic neurons and PD, and reiterate the novel association with oligodendrocytes [ 40 ]. Additionally, the pathway analysis study mentioned previously integrated single-cell expression data to link PD risk to expression patterns in dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons and neural progenitors [ 38 ].…”

Molecular Mechanisms Underlying Synaptic and Axon Degeneration in Parkinson’s Disease

“…Several PD risk genes implicated by Genome-Wide Association Studies (GWAS) also have roles at the synapse including (but not limited to) SH3GL2, SYNJ1, RIMS1, VAMP4, SYT4, ANK2, LRRK2, SNCA, STX1B, SYT11, and VPS35 (Nalls et al, 2014(Nalls et al, , 2019Chang et al, 2017;Blauwendraat et al, 2020;Grenn et al, 2020). GWAS and subsequent analyses of gene-phenotypic trait associations (Heilbron et al, 2019) and cell-type-specific expression patterns discovered an enrichment of risk-associated genes in neurons (Bandres-Ciga et al, 2020;Bryois et al, 2020), as well as oligodendrocytes, astrocytes, and endothelium (Reynolds et al, 2019;Bryois et al, 2020). While cell-type-specific variant-associated changes in gene expression remain unexplored due to the technical challenge of performing single-cell transcriptomics and whole-genome sequencing in the human brain, associations between risk variants and gene expression at the tissue level have been found using quantitative trait loci (QTL) mapping (Nica et al, 2010;Hernandez et al, 2012;Westra and Franke, 2014;Guelfi et al, 2020).…”

A genetic and transcriptomic assessment of theKTN1gene in Parkinson’s disease risk

“…ATG14 function is required for both basal and inducible autophagy but also determines the localization of the autophagy-specific PI3-kinase complex and contributes to autophagosome formation 25 . Interestingly, there is genetic, pathological, and experimental evidence suggesting an important role for autophagy impairment in PD 26,27 .…”